Histone demethylase JMJD3 regulates CD11a expression through changes in histone H3K27 tri-methylation levels in CD4+ T cells of patients with systemic lupus erythematosus

Yin, Heng; Wu, Haijing; Zhao, Ming; Zhang, Qing; Long, Hai; Fu, Siqi; Lu, Qianjin

doi:10.18632/oncotarget.16894

Cited by 28 publications

(9 citation statements)

References 36 publications

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“…KDM6B (or JMJD3) is known to affect activation of germinal center B cells and their differentiation into plasma cells ( Barwick et al., 2018 ), which was shown to occur in this study. This demethylase activity has also been reported for development of rheumatoid arthritis and lupus ( Jia et al., 2018 ; Yin et al., 2017 ). In contrast, DNMT1 promotes DNA methylation by transferring methyl groups to DNA specific CpG structures and is important for T-cell homeostasis ( Lee et al., 2001 ) and regulating B-cell activation ( Lai et al., 2013 ).…”

Section: Discussionsupporting

confidence: 67%

Immunity and autoantibodies of a mouse strain with autistic-like behavior

Uddin

Yao

Mondal

et al. 2020

Brain, Behavior, & Immunity - Health

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Female and male mice of the BTBR T + Itpr3 tf /J (BTBR) strain have behaviors that resemble autism spectrum disorder. In comparison to C57BL/6 (B6) mice, BTBR mice have elevated humoral immunity, in that they have naturally high serum IgG levels and generate high levels of IgG antibodies, including autoantibodies to brain antigens. This study focused on the specificities of autoantibodies and the immune cells and their transcription factors that might be responsible for the autoantibodies. BTBR IgG autoantibodies bind to neurons better than microglia and with highest titer to nuclear antigens. Two of the antigens identified were alpha-enolase (ENO1) and dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST). Surprisingly based on IgG levels, the blood and spleens of BTBR mice have more CD4 + and CD8 + T cells, but fewer B cells than B6 mice. The high levels of autoantibodies in BTBR relates to their splenic T follicular helper (Tfh) cell levels, which likely are responsible for the higher number of plasma cells in BTBR mice than B6 mice. BTBR mice have increased gene expression of interleukin-21 receptor ( I l -21 r ) and Paired Box 5 ( Pax5 ), which are known to aid B cell differentiation to plasma cells, and an increased Lysine Demethylase 6B ( Kdm6b )/DNA Methyltransferase 1 ( Dnmt1 ) ratio, which increases gene expression. Identification of gene expression and immune activities of BTBR mice may aid understanding of mechanisms associated with autism since neuroimmune network interactions have been posited and induction of autoantibodies may drive the neuroinflammation associated with autism.

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Section: Discussionsupporting

confidence: 67%

Immunity and autoantibodies of a mouse strain with autistic-like behavior

Uddin

Yao

Mondal

et al. 2020

Brain, Behavior, & Immunity - Health

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“…We also found that probiotics increased the osteoblastic activity by downregulating miRNA-138 that regulates the aberrant H3K27me3 methylation mark within the promoter region of Tfam. Histone modifications are significant regulators of epigenetic chromatin remodeling and are found to activate gene transcription 48 effectively. Histone 3 lysine 27 methylation 3 (H3K27me3) is one of the critical posttranslational modifications of histones.…”

Section: Discussionmentioning

confidence: 99%

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations

Behera¹,

Ison²,

Voor³

et al. 2021

Theranostics

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Rationale: Manipulation of the gut microbiome can prevent pathologic bone loss. However, the effects of probiotics on mitochondrial epigenetic remodeling and skeletal homeostasis in the high-fat diet (HFD)-linked obesity remains to be explored. Here, we examined the impact of probiotics supplementation on mitochondrial biogenesis and bone homeostasis through the histone methylation mechanism in HFD fed obese mice. Methods: 16S rRNA gene sequencing was performed to study the microbiota composition in the gut and microbial dysbiosis in obese mouse model. High resolution (microPET/CT) imaging was performed to demonstrate the obese associated colonic inflammation. Obese-associated upregulation of target miRNA in osteoblast was investigated using a microRNA qPCR array. Osteoblastic mitochondrial mass was evaluated using confocal imaging. Overexpression of mitochondrial transcription factor (Tfam) was used to investigate the glycolysis and mitochondrial bioenergetic metabolism using Tfam-transgenic (Tg) mice fed on HFD. The bone formation and mechanical strength was evaluated by microCT analysis and three-point bending analysis. Results: High-resolution imaging (µ-CT) and mechanical testing revealed that probiotics induced a significant increase of trabecular bone volume and bone mechanical strength respectively in obese mice. Probiotics or Indole-3-propionic acid (IPA) treatment directly to obese mice, prevents gut inflammation, and improved osteoblast mineralization. Mechanistically, probiotics treatment increases mitochondrial transcription factor A (Tfam) expression in osteoblasts by promoting Kdm6b/Jmjd3 histone demethylase, which inhibits H3K27me3 epigenetic methylation at the Tfam promoter. Furthermore, Tfam-transgenic (Tg) mice, fed with HFD, did not experience obesity-linked reduction of glucose uptake, mitochondrial biogenesis and mineralization in osteoblasts. Conclusions: These results suggest that the probiotics mediated changes in the gut microbiome and its derived metabolite, IPA are potentially be a novel agent for regulating bone anabolism via the gut-bone axis.

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“…JMJD3 is known as a H3K27 demethylase, which regulates the transcription of target genes through H3K27me3 demethylation [ 53 ]. A previous study showed that JMJD3 synergistically regulated the transcription of target genes with the transcription regulator NF-κB/p65 [ 27 ] and emerging evidences demonstrated that NF-κB/p65 was associated with the development of sepsis [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

Sun

Chen

et al. 2021

Stem Cell Res Ther

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Background Exosomal microRNAs (miRs) derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis. Moreover, miR-27b is highly enriched in MSC-derived exosomes. Herein, we aimed to investigate the potential role and downstream molecular mechanism of exosomal miR-27b in sepsis. Methods Inflammation was induced in bone marrow-derived macrophages (BMDMs) by lipopolysaccharide (LPS), and mice were made septic by cecal ligation and puncture (CLP). The expression pattern of miR-27b in MSC-derived exosomes was characterized using RT-qPCR, and its downstream gene was predicted by in silico analysis. The binding affinity between miR-27b, Jumonji D3 (JMJD3), or nuclear factor κB (NF-κB) was characterized to identify the underlying mechanism. We induced miR-27b overexpression or downregulation, along with silencing of JMJD3 or NF-κB to examine their effects on sepsis. The production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 was detected by ELISA. Results miR-27b was highly expressed in MSC-derived exosomes. Mechanistic investigations showed that miR-27b targeted JMJD3. miR-27b decreased expression of pro-inflammatory genes by inhibiting the recruitment of JMJD3 and NF-κB at gene promoter region. Through this, MSC-derived exosomal miR-27b diminished production of pro-inflammatory cytokines in LPS-treated BMDMs and septic mice, which could be rescued by upregulation of JMJD3 and NF-κB. Besides, in vitro findings were reproduced by in vivo findings. Conclusion These data demonstrated that exosomal miR-27b derived from MSCs inhibited the development of sepsis by downregulating JMJD3 and inactivating the NF-κB signaling pathway.

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Histone demethylase JMJD3 regulates CD11a expression through changes in histone H3K27 tri-methylation levels in CD4+ T cells of patients with systemic lupus erythematosus

Cited by 28 publications

References 36 publications

Immunity and autoantibodies of a mouse strain with autistic-like behavior

Immunity and autoantibodies of a mouse strain with autistic-like behavior

Probiotics Stimulate Bone Formation in Obese Mice via Histone Methylations

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

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